Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/56—One oxygen atom and one sulfur atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/60—Three or more oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/69—Benzenesulfonamido-pyrimidines

Definitions

• R and R have the same meaning as in'Formula preparation of sulfonamides of the formula i 3,132,139 r PROCESS non THE PREPARATION or SULFQNA- ,MIDES or run P Y i 1' TYPE Hermann Bretschneider, Innsbrk-Arzl, and Wilhelm Kliitzer and Joachim Schantl, Innsbruck, Austria, assignors to li-iotfmann-La Roche Inc, Nutley, l ⁇ l.J., a
• the present invention relates to a novel process for the whe reinR and'R are lower alkyl groups, preferably those with 1- to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, hexyl, etc.; and R can also be a hydrogen atom or an ---OR group.
• the present process is carried out by removing the -SR group by hydrogenationfrom a compound having the formula 1 c g v R (fR 7 SR ;(II)
• Starting materials with a free amino group in the pposition can be prepared from the coupled products according to known methods for converting an amino group precursor into an amino group.
• Z-methylthio-4-amino-o-methoxy-pyrimidine can be reacted with p-acetarnidobenzenesulfonyl chloride in pyridine at about 7 room temperature to form 2-methy1thio-4-(N -acetylsul- N -acetyl group on this compound can be a 2.5 g. of anhydrous sodium ,ture allowed to stand for one. hourinthe c'old.
• the filtrate yields not is converted into an amino group by known methods, forexarnple, hydrolysis or reduction.
• The. reduction of reducible; groups, such as the nitro group can also, be
• acylated product is convertedi'nto a compound of Formula I containing a 'free amino group by saponification, j;e ,'g-.;by. the addition of an alkali hydroxide, e g. sodium h'droxide to thereaction solution
• an alkali hydroxide e g. sodium h'droxide
• the compound of 1 frnula l can easily'be. recoveredfrom.thealkaline solu than the solation ireaches a of about 5;; .or by intro are the product.
• g m 'fa'terials iin th e pr'ocess o f the. invention can be iprg. is Pin mi Q inidi -the tst i l ,drogry-pyrimidinev through”. irrethylation of the 'hydroXy "groupbymeans of phenyltrirnethylamrnonium chloride, or
• the compounds of Formula I prepared accordingto the process of the invention exhibit high antibacterialactivity, e.g. against staphylococcal, pneumococcal, or
• Example 1 8 g. of 2-methylthio-4-(N -acetylsulfanilamido)-6- methoxy-pyrimidine were added to 150 m1. of water in carbonate. Then about 20 to about. 25 g. of Raney nickel [prepared according to Organic Synthesis 21, 15 (1941)] is added thereto: and the-mixture heated at the boiling point for three hours. . The mixture is cooled, 7 g. of sodium hydroxideadded, and the reaction product saponified by keeping the reaction mixture on a boiling water bath for 11.0.minutes. It is'then filtered hot, and the Raney nickel washed with two portions of 10' ml.
• Raney nickel prepared according to Organic Synthesis 21, 15 (1941)
• pacetyl amidobenzenesulfonyl chloride added at '20 C.
• the mixture becomes colored red-brown in a slightly exothermic'reaction.
• the pyridine is evaporated ofi' at amaximum temperatureof C.
• the 2-rnethylthio ⁇ 4-ainino :6 methoXy-pyrimidinej can be prepared from 2-m'ethylthio-4-amino 6-hyby 'methanolysis of the 6-chlorine atom.
• Example 4 2 g. of 2-methylthio-4-(N -acetyl-sulfanilamido)-5- rnethyl 6-methoxy-pyrimidine are dissolved, while heating gently, in a'soluti-on of 1.5 g. of sodium carbonate and 70 ml. of Walter. 5-6 g. of Raney tnickel are added 5"ml.'of concentrated ammonia, g. of Raney nickel and the mixture heated to 8590 for one hour on a I steam bath. The mixture is treated with charcoal, filtered, andthe. alkaline filtrate acidified to pH 5 with acetic acid. Practically pure crystalline 4-sulfanilamido- S-ethyl-6-methoxy-pyrimidine is obtained thereby; melting point l86-l87 C. (from acetonitrile).
• the 2-methylthio-4-(Nyacetylsulfanilamido)-5-ethyl-6- methoxy-pyrimidine used as the starting material can be obtained as follows:
• Ethylcyanoacetic acid ethyl ester isjcondensed with thiourea to form 2-thio-4-amino-5-ethyl-6-hydroxy-pyrimidine (melting point 299-301 C. from ethanol), which is methylated on the mercapto group with dimethyl sulfate, and the Z-methylthio-4-amino-5-ethyl-6-hydroxypyrimidine (melting point 221-222 C. from dioxane) jobtained thereby is converted to 2-methylthio-4-amino-5- ethyl-6-methoxy-pyrimidine (melting point 102-104 C. from'butyl oxide) by means of"phenyltrimethyl'a'mmonium chloride.
• Example 3 8.6g. of 2-methylthio-4-sulf anilamido-5-ethyl-6-methoxy-pyrimidine are suspended in 80 ml. of water, and 5 thereto and the solution; is refluxed for 2% hours and filrte-red hot. By acidifying the filtrate with dilute hydrochloric acid, there are obtained 1.2 'g. (65%) of 4-(N acetyl sulfanilamido) -5 methyl-6-methoxy-pyrimidine of melting point 228-231 (from water/ethanol).
• the product thus obtained is saponified on a water bath for 1 /2 hours with 12 ml. of 1 N sodium hydroxide soluti-on. 'Aliter coolingand filtration, the filtrate is acidified (Congo red) with dilute hydrochloric acid. The undissolved residue is filtered off. The filtrate is cautiously rendered alkaline by means of concentrated ammonia, whereupon the pH of thesolution is brought to 5-7 with glacial acetic acid. .085 g. (81%) #of 4-sulfanilamido-5- methyl-6-methoxy-pyrimidine of melting point 214-217 (from water/ethanol) is obtained thereby.
• dimethoxy-pyrimidine (arev dissolved in 25 ml. of water and 0.4 g. of anhydrous sodium carbonate, then refluxed hour.
• the catalyst is filtered oif and the filtrate acidified to Con-gored withfhydrochloric ac-id.
• the pH is then broughit'to 5 by means of ammonia, thus causing crystallization.
• 0 t 1.2 g. of p-acetylamidobenzenesuifonyl chloride are added thereto and the mixture is shaken until all the materialis dissoi-ved. The solution is allowed to stand for 22 hours at and the pyridine eliminated in vacuo at 20.
• 2-methyllthio-4-amino-5,6-dimethyl-pyrimidine can in turn be prepared as iollowsz' (a) n-Methoxy-cyanoacetic acid methyl ester is condensed with thiou-rea, the presence of sodium methylate, to form 2-thio-4amino5-methoxy-6-hydroxy-pyrimidine,

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 0
  • NL NL279406D patent/NL279406A/xx unknown
• 1961
  • 1961-06-16 CH CH707361A patent/CH396008A/de unknown
• 1962
  • 1962-05-11 DE DEH45758A patent/DE1218454B/de active Pending
  • 1962-06-07 GB GB22063/62A patent/GB951026A/en not_active Expired
  • 1962-06-07 DK DK252062AA patent/DK98960C/da active
  • 1962-06-07 BE BE618639A patent/BE618639A/fr unknown
  • 1962-06-08 US US200925A patent/US3132139A/en not_active Expired - Lifetime
• 1964
  • 1964-12-26 OA OA51039A patent/OA00944A/xx unknown

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